Intramolecular SN′-type aromatic substitution of benzylic carbonates at their para-position

Article abstract of DOI:10.1021/ol203089k

The benzylic carbonates, which connect with an active methine through an o-phenylene tether at their meta-position, are cyclized by Pd(η³- C₃H₅)Cp-S-Phos catalyst, yielding 3-methyl-9,10- dihydrophenanthrenes. In the catal

Full text of DOI:10.1021/ol203089k

ORGANIC
LETTERS
0
2012
Vol. 14, No. 1
338–341
Intramolecular SN -Type Aromatic
Substitution of Benzylic Carbonates at
their Para-Position
Satoshi Ueno, Sadakazu Komiya, Takeshi Tanaka, and Ryoichi Kuwano*
Department of Chemistry, Graduate School of Sciences, and International Research
Center for Molecular Systems (IRCMS), Kyushu University, 6-10-1 Hakozaki,
Higashi-ku, Fukuoka 812-8581, Japan
rkuwano@chem.kyushu-univ.jp
Received November 17, 2011
ABSTRACT
The benzylic carbonates, which connect with an active methine through an o-phenylene tether at their meta-position, are cyclized by
Pd(η3-C3H5)CpꢀS-Phos catalyst, yielding 3-methyl-9,10-dihydrophenanthrenes. In the catalytic cyclization, the internal nucleophile attacks
not the ortho-carbon but the para-carbon of the benzylic ester. The [3 þ 2] cycloaddition of m-(silylmethyl)benzyl carbonates with alkylidene
0
malonates was developed from the palladium-catalyzed intramolecular SN -type aromatic substitution.
Allylic electrophiles are known to react with nucleo-
philes at their position γ as well as R to the leaving group.1
In contrast, the nucleophilic substitution of benzylic elec-
trophiles normally occurs only on the benzylic carbon and
is accompanied with no γ-substitution,2 although the
electrophilic substrate can be considered an analog of an
allylic compound if its aromatic ring is viewed as an alkene
carbonꢀcarbon double bond. Some research groups,3ꢀ7
including us,8,9 have studied the palladium-catalyzed nu-
cleophilic substitution of benzylic carbonates and carbox-
ylates. The catalytic reaction is believed to proceed through
an (η3-benzyl)palladium(II) intermediate, which is gener-
ated from the oxidative addition of the benzylic substrate to
palladium(0). Analogous with the TsujiꢀTrost reaction,10
the nucleophile might react with the η3-benzyl ligand 0at the
γ-position, i.e. ortho-position. Nevertheless, the SN -type
aromatic substitution has never been reported in the cata-
lytic reactions of benzylic esters to our knowledge.11
(1) A review: Magid, R. M. Tetrahedron 1980, 36, 1901.
(2) Tri- and diarylmethyl chlorides are known to dimerize through
the radical intermediate. In the dimerization, a radical attacks to the
para-position of another one; see: Lankamp, H.; Nauta, W. T.; MacLean,
C. Tetrahedron Lett. 1968, 9, 249.
(3) (a) Legros, J.; Fiaud, J. Tetrahedron Lett. 1992, 33, 2509.
(b) Legros, J.; Toffano, M.; Fiaud, J. Tetrahedron: Asymmetry 1995,
ꢀ
6, 1899. (c) Legros, J.; Primault, G.; Toffano, M.; Riviere, M.; Fiaud, J.
ꢁ
Org. Lett. 2000, 2, 433. (d) Assie, M.; Legros, J.; Fiaud, J. Tetrahedron:
Asymmetry 2010, 21, 1701.
(9) A review: Kuwano, R. Synthesis 2009, 1049.
(4) Fields, W. H.; Chruma, J. J. Org. Lett. 2010, 12, 316.
(5) Torregrosa, R. R. P.; Ariyarathna, Y.; Chattopadhyay, K.;
Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 9280.
(6) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
1360.
(10) (a) Hata, G.; Takahashi, K.; Miyake, A. J. Chem. Soc., Chem.
Commun. 1970, 1392. (b) Atkins, K. E.; Walker, W. E.; Manyik, R. M.
Tetrahedron Lett. 1970, 11, 3821. Reviews: (c) Tsuji, J. Palladium
Reagents and Catalysts; John Wiley & Sons: West Sussex, 2004. (d) Trost,
B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(7) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2010, 132,
15534.
(11) Palladium-catalyzed aromatic substitutions of benzylic chlo-
rides have been reported by Yamamoto and Bao: (a) Bao, M.; Nakamura,
H.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 759. (b) Lu, S.; Xu, Z.;
Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2008, 47, 4366. (c) Peng,
B.; Feng, X.; Zhang, X.; Zhang, S.; Bao, M. J. Org. Chem. 2010, 75,
2619. (d) Peng, B.; Zhang, S.; Yu, X.; Feng, X.; Bao, M. Org. Lett. 2011,
13, 5402. Theoretical study: (e) Ariafard, A.; Lin, Z. J. Am. Chem. Soc.
2006, 128, 13010.
(8) (a) Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc.
2003, 125, 12104. (b) Kuwano, R.; Kondo, Y. Org. Lett. 2004, 6, 3545.
(c) Kuwano, R.; Kondo, Y.; Shirahama, T. Org. Lett. 2005, 7, 2973.
(d) Yokogi, M.; Kuwano, R. Tetrahedron Lett. 2007, 48, 6109. (e)
Kuwano, R.; Kusano, H. Chem. Lett. 2007, 36, 528. (f) Kuwano, R.;
Kusano, H. Org. Lett. 2008, 10, 1979.
r
10.1021/ol203089k
Published on Web 12/02/2011
2011 American Chemical Society

In this context, we envisioned that the Pd-catalyzed
substitution might occur at the ortho-position if a nucleo-
philic moiety was installed in the benzylic substrate on its
meta-carbon through anappropriate tether(Figure1). The
tether will restrict the intramolecular nucleophilic attack
on the benzylic carbon (path a), enforcing the aromatic
substitution (path b).12 This paper describes the reactions
of the meta-substituted benzylic carbonates with a Pd
catalyst. As we had expected, the Pd catalyst successfully
spectator ligand (entries 6 and 7). Furthermore, a biaryl
monophosphine ligand13 L1 was found comparable to
DPPF (entry 8). The o-phenyl substituent of L1 may be
0
critical for the SN -type aromatic substitution. A Cy2-
PhPꢀpalladium complex, which lacks the o-substituent,
produced 2a in only 11% yield (entry 9). The formation of
2a was remarkably improved by use of biarylphosphine
ligands bearing electron-rich substituents on their o-aryl
group (entries 11ꢀ13). In particular, L3 and L414 enabled
0
cyclized the substrates through the SN -type aromatic
substitution. However, the substitution occurred not at
the ortho-position but at the para-position.
Table 1. Effect of Solvent and Ligand on the Reaction of 1aa
Figure 1. Substrate Design for SN0-Type Aromatic Substitution.
convn
(%)
yieldb
(%)
An o-phenylene skeleton would be suitable for the tether
because its rigid structure would be favorable for position-
ing the internal nucleophile around the ortho-position of
the benzyl ester. In accordance with the idea, we designed
the m-substituted benzyl ester 1 to achieve the intramole-
entry
ligand
solvent
THF
1c
DPPFd
DPPFd
DPPFd
DPPFd
DPEphosd
DPPBd
DPPPentd
L1
99
15
6
2c
toluene
1,4-dioxane
DMF
90
3c
76
7
4c
>99
>99
>99
96
52
16
78
81
40
11
0
5c
DMF
0
cular SN -type aromatic substitution. The substrate 1a was
6c
DMF
heated in THF at 80 °C in the presence of N,O-bis-
(trimethylsilyl)acetamide (BSA), potassium acetate, and
[Pd(η3-C3H5)Cp]ꢀDPPF catalyst, which is the most effec-
tive for the nucleophilic substitution of benzyl carbonates
with malonate carbanions in our previous reports (Table 1,
entry 1).8a,b Contrary toour expection, noformation of the
7c
DMF
8
DMF
64
9
PCy2Ph
PCy3
L2
DMF
48
10
11
12
13
14
15e
16e
DMF
29
DMF
>99
>99
>99
>99
>99
>99
77
89
88
13
89f
97f
L3
DMF
L4
DMF
1-methyl-9,10-dihydrophenanthrene
3 was observed,
L5
DMF
while the substrate almost disappeared. Compound 1a
mainly underwent the intermolecular nucleophilic substi-
tution to form oligomeric products. To our surprise, a
small amount of 3-methyldihydrophenanthrene 2a was
detected in the reaction mixture (Table 1, entry 1). The
observation indicates that the internal malonate in 1a
attacks the para-carbon in preference to the ortho-carbon
in the case of the intramolecular reaction. With the aim to
increase the cyclization, 1a was heated under various
reaction conditions. A more polar solvent seems favorable
for the cyclization (entries 1ꢀ4). DMF is the solvent of
choice for the intramolecular reaction. The selectivity as
well asthe conversion in the reaction of 1ais affected by the
phosphine ligand on palladium. The DPEphos ligand
makes the undesirable oligomerization more predominant
(entry 5). The desired cyclization was preferable to the side
reaction when DPPB or DPPPent was employed as the
L3
DMF
L4
DMF
a Reactions were conducted on a 0.1 mmol scale in 0.2 mL of solvent
at 80 °C for 2 h. The ratio of 1a/[Pd]/ligand/BSA/KOAc was
100:5.0:11:110:10. b Determined by GC analysis (average of two runs).
c The ratio of [Pd]/ligand was 1.0:1.1. d The structures of the bidentate
ligands are shown in Table 3. e The reactions were conducted on a 0.4
mmol scale in DMF (0.8 mL) with a 1.0 mol % catalyst loading ([Pd]/
ligand = 1.0:2.2). f Isolated yield.
the palladium catalyst to selectively promote the intramo-
0
lecular SN -type aromatic substitution of 1a, giving 2a in
high yield. Replacing cyclohexyl with tert-butyl on the
phosphorus of L4 increased the undesirable intermolecular
reaction (entry 14). The catalyst loading can be reduced to
(13) A review for biaryl monophosphine: Surry, D.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 6338.
(14) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
(12) A review of aromatic nucleophilic substitution: Burnett, J. F.;
Zahler, R. E. Chem. Rev. 1951, 49, 273.
Angew. Chem., Int. Ed. 2004, 43, 1871.
Org. Lett., Vol. 14, No. 1, 2012
339

1 mol % without degradation of the yield of 2a (entries
15 and 16).
4-position was subjected to the Pd-catalyzed reaction to
allow the formation of the ortho-substitution product 3.
However, the reaction yielded only oligomers of the p-
methylated substrate.
Substrates 1bꢀ1g bearing an active methine other than
0
dimethyl malonate underwent the intramolecular SN -type
0
aromatic substitution in the presence of the L4ꢀPd cata-
lyst (Table 2, entries 1ꢀ6). Ethyl ester 1b as well as 1a was
cyclized in high yield, although the cyclization of 1b
required a longer reaction time for its completion. In the
reaction of isopropyl ester 1c, the cyclization product 2c
was obtained in only 39% yield with a 1 mol % catalyst
loading. Efficient production of 1c was achieved by in-
creasing the catalyst loading to 5 mol %. The intramole-
cular nucleophilic attack of the stabilized carbanion to the
aromatic ring in 1 may be sensitive to the steric hindrance
around the nucleophilic carbon. The Pd-catalyzed cycliza-
tion is applicable to the substrates 1dꢀ1g bearing either
β-keto- or R-cyanocarboxylate in place of malonate. The
benzyl esters 1h and 1j, which have a methoxy or fluoro
group at their 5-position, also gave the cyclization pro-
ducts 2hand 2jin97% and 67% yields, respectively(entries
7 and 9). Meanwhile, a 5-methyl substituent of 1i caused
The Pd-catalyzed intramolecular SN -type aromatic sub-
stitution of 1 would proceed through the pathway as
shown in Scheme 1. Substrate 1 is deprotonated by BSA
and potassium acetate to give its stabilized carbanion 10
before it reacts with the catalyst. The L4ꢀPd(0) species
cleaves the benzylic CꢀO bond of 10, forming zwitterionic
(η3-benzyl)palladium 4. The carbanion in intermediate 4 is
hindered from attacking the ortho-carbon of the η3-benzyl
ligand by the bulkiness of the L4-ligated palladium. There-
fore, the internal nucleophile reacts with the para-carbon
in the manner of an SN20 pathway. The resulting product 5
is aromatized through a 1,5-hydride shift15 to produce
3-methyl-9,10-dihydrophenanthrene 2. The palladium
may be possible to form η3-benzyl complex 6 with the
6-carbon of 1. However, the intermediate 6 is supposed
unfavorable for the intramolecular SN20-type reaction,
because substrate 1l gave the cyclization product in lower
yield than 1k (Table 2, entries 10 and 11). The 2-methyl
group of 1l may obstruct the formation of intermediate 4.
Table 2. Intramolecular SN0-Type Aromatic Substitution of 1a
Scheme 1. A Possible Pathway of the Cyclization of 1
time
(h)
yieldb
(%)
entry
R1
R2
Et
R3
1
1c,d
2d
3d
4d
5
EtO2C
i-PrO2C
MeCO
i-PrCO
PhCO
H
H
H
H
H
H
1b
1c
1d
1e
1f
24
6
98
77
63
74
86
>99
97
16
67
60
25
i-Pr
Et
4
Me
Et
4
4
6
NC
Me
Me
Me
Me
Me
Me
1g
1h
1i
4
7
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
5-MeO
5-Me
5-F
6
0
The above SN -type aromatic substitution allowed us to
8
115
2
9
1j
come up with the [3 þ 2] cycloaddition of m-(silylmethyl)
benzyl carbonates 7 and benzylidene malonates 8
(Scheme 2).16,17 The fluoride-mediated 1,4-addition of
the benzylsilane 7 to the R,β-unsaturated carbonyl
would afford the benzyl ester 9,18 which is tethered to
the malonate carbanion with an alkyl chain. The [3 þ 2]
10
11
6-Me
2-Me
1k
1l
7
4
a Reactions were conducted on a 0.2 mmol scale in DMF (0.4 mL) at
100 °C. The ratio of 1/[Pd]/L4/BSA/KOAc was 100:5.0:11:110:10 unless
otherwise noted. b Isolated yield. c The reaction was conducted on a
0.4 mmol scale in DMF (0.8 mL) with a 1.0 mol % catalyst loading.
d The reactions were conducted at 80 °C.
(15) Jaeger, C. W.; Kornblum, N. J. Am. Chem. Soc. 1972, 94, 2545.
(16) The [4 þ 2] cycloadditions of o-(silylmethyl)benzyl esters with
double bonds: (a) Kuwano, R.; Shige, T. J. Am. Chem. Soc. 2007, 129,
3802. (b) Ueno, S.; Ohtsubo, M.; Kuwano, R. J. Am. Chem. Soc. 2009,
131, 12904. (c) Ueno, S.; Ohtsubo, M.; Kuwano, R. Org. Lett. 2010, 12,
4332.
(17) Selected examples of transition-metal catalyzed [3 þ 2] cycload-
dition with carbonꢀcarbon double bonds giving indan skeletons:
(a) Lautens, M.; Mancuso, J. Org. Lett. 2002, 4, 2105. (b) Nishimura,
T.; Yasuhara, Y.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 7506. (c) Yu,
X.; Lu, X. Org. Lett. 2009, 11, 4366.
the low yield of 2i (entry 8). The correlation between the
yield of 2 and the 5-substituent of 1 indicates that the SN20-
type aromatic substitution is affected by the steric factor
rather than the electronic property of the 5-substituent.
2,3-Dimethyldihydrophenanthrene 2k was obtained in
60% yield from an o-methylbenzyl ester 1k, while another
o-methylated substrate 1l failed to be converted to 3,4-
dimethyldihydrophenanthrene 2l in good yield (entries 10
and 11). The substrate 1 bearing a methyl group at the
(18) Ricci, A.; Fiorenza, M.; Grifagni, M. A.; Bartolini, G.; Seconi,
G. Tetrahedron Lett. 1982, 23, 5079.
340
Org. Lett., Vol. 14, No. 1, 2012

cycloaddition product 10 might be obtained if the in situ
generated 9 was cyclized in the same way as 1.
Table 3. Effect of Ligand on the Reaction of 7 with 8a
Scheme 2. Design of the [3 þ 2] Cycloaddition of 7 with 8
entry
ligand
L4
yield, %b
1c
2c
3c
4
23
L3
33
L2
35
A solutionof7and 8 in DMF was heated at 80 °C for3 h in
the presence of cesium fluoride and the L4ꢀpalladium catalyst
(Table 3, entry 1). Formation of the desired [3 þ 2] cycloaddi-
tion product 10 was observed in the resulting mixture with GC
analysis, but its yield was only 23%. To improve the Pd
catalyst, a series of phosphine ligands other than L4
were evaluated for the reaction of 7 with 8. In contrast to
the cyclization of 1, bidentate bisphosphine ligands are more
suitable for the catalytic cycloaddition than Buchwald-type
biarylphosphines. A DPPBꢀPd catalyst produced 10 in 42%
yield at 3 h (entry 5). The substrate 7 completely disappeared
at 3 h, while a longer reaction time led to a higher yield of the
cycloaddition product. This suggests that the [3 þ 2] cycload-
dition proceeds through the sequence of the fluoride-mediated
DPPP
DPPB
DPPPent
DPPF
DPEphos
DPPB
31
5
42 (57)d
23
6
7
34
8
9e
37
49f
a Reactions were conducted on a 0.1 mmol scale in 0.4 mL of DMF at
80 °C for 3 h. The ratio of 7/8/[Pd]/ligand/CsF was 120:100:5.0:5.5:100.
b Determined by GC analysis (average of two runs). c The ratio of [Pd]/
ligand was 1.0:2.2. d GC yield at 24 h. e The reaction was conducted on a
0.4 mmol scale for 24 h. f Isolated yield.
In conclusion, we successfully proved that benzyl
carbonates are able to react with a nucleophile on
their aromatic ring in the manner of an SN0 pathway in
the presence of a palladium catalyst. The aromatic
nucleophilic substitution requires an internal nucleo-
phile, which is installed in the electrophilic substrate
at the meta-position. The nucleophilic moiety attacks
the para-position of the benzyl ester exclusively,
giving 3-methyldihydrophenanthrene. Furthermore,
the [3 þ 2] cycloaddition of a m-(silylmethyl)benzyl
carbonate with a benzylidene malonate was devel-
oped from the palladium-catalyzed SN0-type aromatic
substitution.
1,4-addition18 and the Pd-catalyzed SN -type aromatic sub-
0
stitution as shown in Scheme 2. To confirm the pathway, the
reaction of 7 with 8 was conducted in the absence of the Pd
catalyst (eq 1). As expected, the benzyl silane 7 added to the
electron-deficient alkene 8 to give intermediate 9 in 51%
isolated yield without formation of 10. The resulting benzyl
ester 9 was cyclized by the DPPBꢀPd catalyst to form 10
(eq 2). The cyclization step can proceed in the absence of
cesium fluoride, but the fluoride ion works as a base to
0
facilitate the SN -type aromatic substitution.
Acknowledgment. This work was supported by a Grant-
in-Aid for the Global COE Program, “Science for Future
Molecular Systems” from MEXT.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic characterization for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
341